A Positive-Controlled Phase III Study Evaluating Recombinant Erythropoietin Stimulating Protein Injection (CHO Cell) in Hemodialysis Patients with Anemia Due to Chronic Renal Failure

Recombinant Erythropoietin Stimulating Protein Injection (CHO Cell)（abbreviated as rESP）is a recombinant erythropoietin produced via gene recombination technology to , incorporating targeted mutations into the rHuEPO gene to introduce three additional N-glycosylation sites.  Compared to natural rhEPO, rESP exhibits over 50% higher sialic acid content. This modification preserves biological activity while enhancing stability and prolonging half-life, allowing for less frequent dosing and improvedconvenience in clinical use.

This randomized, open-label, parallel-controlled phase III trial was conducted across 44 centers in China. The study comprised  a 16-week preparation period, a 4-week screening period, a 24-week maintenance therapy period (weeks 1 to 24) and an 8-week efficacy evaluation period (weeks 25 to 32). Patients already on stable doses of short-actingerythropoietin with  steady hemoglobin levels (100 to 120 g/L) proceeded directly to the screening period at the investigators’ discretion. Patients who entered the preparation period received rhEPO intravenously one to three times weekly, with doses based on and adjusted according to hemoglobin concentrations on at least one measurement per month. Eligible patients with  mean hemoglobin concentrations between 100 and 120 g/L during the screening were randomized in a 1:1 ratio to receive either rhEPO or rESP. Randomization was performed centrally via an Interactive Web Response System (IWRS) , stratified by baseline rhEPO dose(<8000 IU per week, ≥8000 and ≤16000 IU per week, and >16000 IU per week) and mean hemoglobin concentrations (≥100 and ≤110 g/dL vs. >110 and ≤120 g/L) based on two measurements at least two weeks apart during the screening period. The starting dose of short-acting erythropoietin was based on the dose and frequency at randomization. The starting dose of rESP was 50 μg, administered intravenously every other week (QOW) from weeks 1 through 32. The primary efficacy endpoint was the mean change in hemoglobin from the baseline to the evaluation period  (average of measurements from weeks 25–32). Secondary efficacy endpoints included the proportion of patients maintaining hemoglobin  within the target range (100-120 g/L), the proportion of patients whose hemoglobin levels failed to stay in the target range despite a ±25% dose changeand the proportion of patients with unstable hemoglobin  during the evaluation period.

Of screened 548 patients, 300 were randomized. All of these patients received at least one dose of the study drugs and were included in the Full Analysis Set ( FAS): 147 in the rESP group and 153 in the rhEPO group.Meanhemoglobin (Hb) levels of the rESP group and the rhEPO group at each visit are shown in Figure 1A and 1B. Mean (SD) hemoglobin during  week 25 -32 was 108.64±7.79 g/L (IQR 102.75 to 114.25)for rESP group and 108.47±7.82 g/L (IQR 104.25 to 113.75) for rhEPO group, with  mean changes from baseline of -1.87±8.00 g/L and -1.85±8.92 g/L , respectively..Adjusted mean (SE) hemoglobin  was 108.73±0.78 g/L  (rESP) and 108.61±0.75 g/L (rhEPO), with a least squares mean (LSM) difference of 0.12 (95% CI -1.74 to 1.98; MMRM P = 0.901). The adjusted LSM change from baseline hemoglobin was -1.46±1.00 g/L for rESP p and −1.58±0.96 g/L for rhEPO, with an adjusted mean difference of 0.12 g/L (95%CI -1.82 to 2.06). The lower limit of 95%CI exceeded the non-inferiority margin, confirming non-inferiority of rESP to rhEPO.. Consistency was observed across all predefined subgroups (Figure 2). Missing data minimal, and sensitivity analysis supported the robustness of the primary outcome. The proportion  of patients maintaining target  hemoglobin was 64.6% (95/147) with rESP and 60.1 (92/153) with rhEPO duringweek 25 -32 (OR = 1.22, 95% CI, 0.76 to 1.96;CMH χ2 test P = 0.413) (Table 1). Among patients who had a ≥ 25% dose increase or reduction, the percentage of patients whose hemoglobin concentration failed to attain the target range was 2.7% (4/147) in the rESP group and 3.9% (6/153) in the rhEPO group (OR = 0.68, 95% CI 0.19 to 2.44;CMH χ2 test P = 0.548). Unstable hemoglobin levels was observed in 31.3% (46/147) in the rESP group and 30.7 (47/153) in therhEPO group (OR=1.05, 95% CI 0.64, 1.73; CMH χ2 test P = 0.849). No  notable differences (≥5%) between the two groups with regard to the rates of individual adverse events, except for palpitations (8.2% with rESP vs.  1.3% withrhEPO). Treatment-related adverse events were infrequent in both groups, reported by 22.4% (33/147) of patients receiving rESP, as compared with and 17.0% (26/153) of those receiving rhEPO. Hypertension occurred in 4.1% (6/147) o and 5.2% (8/153) , respectively (Table 2).  All subjects tested negative for ADA.

Figure 1 Mean Hb (± 95%CI) by Treatment Group and Visit.Full Analysis Set(A);Per Protocol Set(B)

Figure 2 Forest Plot of the Mean Hb Change from Baseline to the Evaluation Period - Full Analysis Set

Table 1 Maintenance rate of target Hb concentration during the evaluation period (Weeks 25-32)-FAS

Note: The percentage calculation is based on the number of participants in the full analysis set of each group.

[1] The 95% confidence interval (CI) was calculated using the exact (Clopper-Pearson) method.

[2] The CMH chi-square test was used to compare the proportions of participants between groups, with stratification factors considering the randomization stratification factors: baseline EPO dosage (<8000 IU/week, 8000–16000 IU/week [inclusive of both ends], >16000 IU/week) and mean Hb concentration during the screening period (100–110 g/L [inclusive of both ends], 110–120 g/L [excluding 110 g/L, inclusive of 120 g/L]). Missing Hb values during the evaluation period (Weeks 25–32) were imputed as "Hb concentration not within the target range." 

rESP administered every other week demonstrates efficacy non-inferior to rhEPO given one to three times weekly for maintaining hemoglobin in anemia patients with chronic kidney disease on hemodialysis. The safety profile of rESP is favorable and manageable,  with no significant difference in adverse events compared to rhEPO, consistent with known the adverse reactions reported of erythropoietin therapies. In summary, rESP is comparable to rhEPO in both efficacy and safety for maintenance treatment in anemic patients with chronic renal failure undergoing hemodialysis.